The high incidence of keratoconjunctivitis sicca in the population of postmenopausal women is attended by symptoms ranging from mild foreign body sensation to frank pain and visual loss due to ocular surface abnormalities.
The standard treatment with artificial lubricants, which provides temporary symptomatic relief in most cases does not, however, address the cause of the dry eyes. While there has been described treatment of post menopausal females with dry eye syndrome using oral Premarin therapy, the oral or parenteral administration of estrogen can frequently produce side effects such as vaginal bleeding, breast tenderness and other undesired effects and the therapeutic effects derived from oral therapy are minimal. This result is now understood as a result of studies showing that there are very few estrogen receptors in the conjunctiva relative to other tissues of the body (Gans, L. A., et al., Am. J. Ophthalmol. 109(4):474-477 (1990)). Further, such oral or parenteral administration implicates the entire body structure in an indeterminate effort to secure an effect in a localized area (the eye), in the absence of any data relating the level of estrogen introduced into the blood stream to the level, if any, resulting in the tear fluid (it is known generally, that estrogen concentrations in the eye to be in the range of about 10% of serum levels). Conservative medicine would indicate the desirability of limiting the specific effect of the hormone to the recipient site if possible. One possible method of accomplishing this is through the use of topically applied steroids, in drop form. One early reference (Bohigian, G. Handbook of External Diseases of the Eye (Alcon, Inc.) 1980, p. 79) did refer to the use of "special drops" for treating KCS which in fact, contained conjugated estrogens, however, in a declaration during prosecution of U.S. Pat. No. 5,041,434 issued to Lubkin (reissued as U.S. Pat. No. Re. 34,578) and hereby incorporated by reference, Dr. Bohigian stated that the concentration of estrone in the drops was 0.0066% by weight and that it was not effective in alleviating any symptoms. In contrast, the U.S. Pat. No. Re. 34,578 patent of Lubkin showed that treatment of dry eye syndrome or KCS was shown to be effective using a form of estrogen in solution at concentrations of at least 0.1 mg/mL or 0.1% (w/v).
Further studies since about 1990 have shown that estrogen is a component of human tears and that it may play a role in ophthalmic changes in ocular tissue (Kramer, P. et al., Ophthalmol. 1990 97:303-307; Metka, M. et al., Maturitas1991 14:3-8). Other studies, even more recently, have intimated that post-menopausal patients given low systemic doses of estriol (a hydroxylated form of 17-.beta.-estradiol) at a dose of 0.25 mg per day, or that even near homeopathic concentrations of 17-.beta.-estradiol (0.00025%) in drops applied every 6 hours (in women already taking 2 mg estriol valerate daily by mouth) gave varying or marginal improvement in corneal lens transmittance and autofluorescence (Benitez de Castillo, et al., Ophthalmol. 1997 104:970-973).
While it has been shown in the U.S. Pat. No. Re. 34,578 patent that eye drops with concentrations of 17-.beta.-estradiol in solution of at least 0.1% or greater are effective in treating the symptoms of KCS in post-menopausal women even in the absence of concomitant oral estrogen there is currently no available treatment for KCS which uses 17-.beta.-estradiol in solution at concentrations below 0.1%. The invention discloses that such a concentration is extremely useful medically. The present invention shows that the effective concentration of 17-.beta.-estradiol in solution can be as low as at least 0.05% to about 0.1% and continue to be effective regardless of the presence or absence of concomitant oral estrogen therapy in post-menopausal women. This lower dose range is especially useful in providing eye drops that will contain a concentration of 17-.beta.-estradiol that is low enough to be both safe and effective (the medical aspect) yet has the potential to be approved by the FDA for use in non-prescription (OTC) based formulations (the commercial aspect). One can also significantly decrease any potential systemic absorption of estrogen from the present invention by combining the use of the drops with a punctal plug. A punctal plug is a small device which fits inside the punctum lacrimale of the eye and prevents tears from draining into the nasophayngeal cavity through the lacrimal canaliculi. The result of using such a plug is that the tears do not drain away from the corneal surface allowing a greater buildup of lacrimal fluid around the eye. Use of such a plug can either be temporary or permanent and has been used to alleviate eye dryness in patients.
Furthermore, dry-eye syndrome also manifests itself in pre-menopausal women who have hormonal abnormalities including insufficient estrogen production. Typically, these patients often present complaints to their ophthalmologists about the inability to wear contact lenses because of their extreme discomfort. Only upon further examination is the hormonal imbalance identified. The present invention is useful in treating the physical conditions described, but its use should not be considered to be limited to only those listed above.